The proposed research will investigate the mechanisms of negative inotropic action of inhalation anesthetic agents using skinned fiber preparations. The evidence of direct myocardial depression by inhalation anesthetic agents is clear, but the sites and nature of this depression on the normal contractile process have not been determined. Although there is evidence suggesting that the calcium involved in the contractile process may be affected, there is no demonstration of a cause-effect relationship. We propose to study the effects of inhalation anesthetic agents on the calcium-activated tension development in mechanically disrupted cardiac papillary muscle cells (skinned fiber) from the rabbit. Using skinned muscle fiber preparations, the anesthetic effects at the molecular level and on mechanical contraction can be demonstrated simultaneously. We will study the anesthetic effects on Ca2 ion activated tension development of (A) Ca-binding the regulatory and contractile proteins and (B) Ca release from sarcoplasmic reticulum (SR). We will determine the anesthetic effects on Ca-binding the regulatory and contractile proteins by measuring: (a) changes in submaximum Ca2 ion-activated tension development at pCa equals 5.6 to 4.8 and (b) changes in maximum Ca2 ion-activated tension development at pCa equals 3.6. We will establish the anesthetic effects on Ca release from SR by measuring changes in tension development from Na ions-, caffeine-, or Cl negative ions -induced Ca2 ions release. The inhalation anesthetic agents to be studied are halothane, nitrous oxide, enflurane, isoflurane and diethyl ether. Dose-response relationship of the anesthetic agents will be determined on the above two mechanisms of contractile process. The elucidation of the mechanisms of anesthetic-induced myocardial depression of various anesthetic agents will provide better understanding of how inhalation anesthetics alter function in man, permitting a more rational use of these drugs.